Thiazole derivatives having CB1-antagonistic, agonistic or partial agonistic activity

ABSTRACT

Computer game systems respond to the spatial state of a pointing device. Changes in the spatial state of a hand held or mobile unit, or plurality of units drive a game scheme maintained in a computer. Position and attitude of the mobile device cause program branching functions which are bases upon a game rule set. In example, a game scheme executed on a computing apparatus may be incorporated into a mobile telephone having a GPS and electronic compass. Physical states relating to position and pointing attitude of the telephone as described in part by position or attitude parameters, drives computer programming code to takes actions which depend on measured position and attitude values thus making computer games for mobile users are made highly interactive. User gestures including simple pointing actions allow a user to express desires to a computer in an express and direct fashion. These games have many features which cannot be found in more traditional handheld computer games which do not take into consideration the spatial state of an object controlled by a player-user

The present invention relates to a group of thiazole derivatives, tomethods for the preparation of these compounds, and to pharmaceuticalcompositions containing one or more of these compounds as an activecomponent.

The above mentioned thiazole derivatives are potent cannabinoid (CB₁)receptor antagonists, CB₁ receptor agonists or CB₁ receptor partialagonists, with utility for the treatment of psychiatric and neurologicaldisorders and other diseases involving cannabinoid CB₁neurotransmission.

4,5-Diarylthiazole derivatives have been described in EP 388909 and EP377457 as 5-lipoxygenase inhibitors for the treatment of thrombosis,hypertension, allergy and inflammation. The exemplified structurestherein all contain two phenyl rings which are p-substituted with amethoxy, fluoro, methylthio or methylsulfinyl group. WO 9603392describes sulfonylaryl-arylthiazoles for inflammation and pain,arthritis or fever as inflammation-associated disorders. JP 05345772relates to 4,5-diarylthiazoles as acetyl cholinesterase inhibitors, andJP 04154773 describes 4,5-diarylthiazoles having analgesic,antiinflammatory and antipyretic action.

It has now surprisingly been found that the 4,5-diarylthiazolederivatives of the formula (I), pro-drugs thereof and salts thereof

wherein

-   -   R represents a hydrogen atom or a substituent X from the group        branched or unbranched C₁₋₃-alkyl or alkoxy, hydroxy, halogen,        trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,        amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl        (C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,        trifluoromethylsulfonyl, sulfamoyl, branched or unbranched        alkyl(C₁₋₃)sulfonyl, carboxyl, cyano, carbamoyl, branched or        unbranched dialkyl(C₁₋₃) aminosulfonyl, branched or unbranched        monoalkyl(C₁₋₃)-aminosulfonyl and acetyl,    -   R₁ is a hydrogen atom or represents 1-4 substituents X, wherein        X has the abovementioned meaning,    -   R₂ represents a phenyl, thienyl, pyridyl or pyrimidinyl group,        which groups may be substituted with 1-4 substituents X, wherein        X has the abovementioned meaning or R₂ represents naphtyl,    -   R₃ represents a hydrogen atom or a branched or unbranched C₁₋₁₀        alkyl or cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl        group which aromatic rings may be substituted with 1-5        substituents Z, which can be the same or different, from the        group branched or unbranched C₁₋₃-alkyl or alkoxy, hydroxy,        halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy,        nitro, amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl        (C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,        dimethylsulfamido, branched or unbranched C₁₋₃-alkoxycarbonyl,        carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl        and acetyl, or R₃ represents a pyridyl or thienyl group,    -   R₄ represents branched or unbranched C₁₋₁₀ alkyl or        cycloalkyl-alkyl group, branched or unbranched C₁₋₁₀ alkoxy,        C₃₋₈ cycloalkyl, C₅₋₁₀ bicycloalkyl, C₆₋₁₀ tricycloalkyl,        branched or unbranched C₃₋₁₀ alkenyl, C₅₋₈ cycloalkenyl, which        groups may contain one or more heteroatoms from the group (O,        N, S) and which groups may be substituted with a hydroxy group,        1-3 methyl groups, an ethyl group or 1-3 fluoro atoms, or R₄        represents a phenyl, benzyl or phenethyl group which aromatic        rings may be substituted with 1-5 substituents Z, wherein Z has        the abovementioned meaning, or R₄ represents a pyridyl or        thienyl group, or R₄ represents a group NR₅R₆ wherein    -   R₅ and R₆ together with the nitrogen atom to which they are        attached form a saturated or unsaturated, monocyclic or        bicyclic, heterocyclic group having 4 to 10 ring atoms, which        heterocyclic group contains one or more heteroatoms from the        group (O, N, S) and which heterocyclic group may be substituted        with a branched or unbranched C₁₋₃ alkyl, hydroxy or        trifluoromethyl group or a fluoro atom, or    -   R₃ and R₄—together with the nitrogen atom to which they are        attached—form a saturated or unsaturated, monocyclic or        bicyclic, heterocyclic group having 4 to 10 ring atoms, which        heterocyclic group contains one or more heteroatoms from the        group (O, N, S) and which heterocyclic group may be substituted        with a branched or unbranched C₁₋₃ alkyl, hydroxy or        trifluoromethyl group or a fluoro atom,        are potent antagonists, agonists or partial agonists of the        cannabinoid CB₁ receptor.

A pro-drug is an inactive compound, which when absorbed is convertedinto an active form (Medicinal Chemistry: Principles and Practice, 1994,ISBN 0-85186-494-5, Ed.: F. D. King, p. 216).

Due to the potent CB₁ receptor activity the compounds according to theinvention are suitable for use in the treatment of psychiatric disorderssuch as psychosis, anxiety, depression, attention deficits, memorydisorders, cognitive disorders, appetite disorders, obesity, addiction,appetence, drug dependence and neurological disorders such asneurodegenerative disorders, dementia, dystonia, muscle spasticity,tremor, epilepsy, multiple sclerosis, traumatic brain Injury, stroke,Parkinson's disease, Alzheimer's disease, epilepsy, Huntington'sdisease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy,craniocerebral trauma, stroke, spinal cord injury, neuroinflammatorydisorders, plaque sclerosis, viral encephalitis, demyelinisation relateddisorders, as well as for the treatment of pain disorders, includingneuropathic pain disorders, and other diseases involving cannabinoidneurotransmission, including the treatment of septic shock, glaucoma,cancer, diabetes, emesis, nausea, asthma, respiratory diseases,gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovasculardisorders.

The affinity of the compounds of the invention for cannabinoid CB₁receptors was determined using membrane preparations of Chinese hamsterovary (CHO) cells in which the human cannabinoid CB₁ receptor is stablytransfected in conjunction with [³H]CP-55,940 as radioligand. Afterincubation of a freshly prepared cell membrane preparation with the[³H]-ligand, with or without addition of compounds of the invention,separation of bound and free ligand was performed by filtration overglassfiber filters. Radioactivity on the filter was measured by liquidscintillation counting.

The cannabinoid CB₁ receptor antagonistic, agonistic or partialagonistic activity of compounds of the invention was determined byfunctional studies using CHO cells in which human cannabinoid CB₁receptors are stably expressed. Adenylyl cyclase was stimulated usingforskolin and measured by quantifying the amount of accumulated cyclicAMP. Concomitant activation of CB₁ receptors by CB₁ receptor agonists(e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-inducedaccumulation of cAMP in a concentration-dependent manner. This CB₁receptor-mediated response can be antagonised by CB₁ receptorantagonists or partial agonists such as the compounds of the invention.

Cannabinoid receptor agonistic or partial agonistic activity ofcompounds of the invention can be determined according to publishedmethods, such as assessment of in vivo cannabimimetic effects (Wiley, J.L. et al., J. Pharmacol. Exp. Ther. 2001, 296, 1013).

Cannabinoid receptor antagonists may behave as inverse agonists(Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R1-R2).

The invention relates both to racemates, mixtures of diastereomers andthe individual stereoisomers of the compounds having formula (I).

The compounds of the invention can be brought into forms suitable foradministration by means of usual processes using auxiliary substancesand/or liquid or solid carrier materials.

A suitable synthesis for the compounds according to the presentinvention is the following:

Synthesis Route A

Step 1 of Route A

Ester hydrolysis of a compound having formula (II) wherein R₇ representsa branched or unbranched alkyl group (C₁₋₄) or benzyl group.

This reaction gives a compound having formula (III)

wherein R, R₁ and R₂ have the meanings as described hereinabove.

The compounds of the invention having formula (II), wherein R₇represents a branched or unbranched alkyl group (C₁₋₄) or benzyl groupcan be obtained according to methods known, for example:

-   a) Organic Reactions, Vol. VI, (1951), p. 367409, Ed. R. Adams, John    Wiley and Sons Inc., New York-   b) J. S. Carter et al., Bioorg. Med. Chem. Lett. (1999), 9,    1167-1170-   c) T. T. Sakai et al., Bioorg. Med. Chem. (1999), 7, 1559-1566-   d) A. Tanaka et al., J. Med. Chem. (1994), 37, 1189-1199-   e) J. J. Talley et al., WO 9603392: Chem. Abstr. 125, 33628-   f) V. Cecchetti et al., Bioorg. Med. Chem. (1994), 2, 799-806    Step 2 of Route A

Reaction of a compound having formula (III) with a compound havingformula R₃R₄NH wherein R₃ and R₄ have the meanings as describedhereinabove via activating and coupling methods such as formation of anactive ester, or in the presence of a so-called coupling reagent, suchas for example, DCC, HBTU, BOP, CIP (2-chloro-1,3-dimethylimidazoliniumhexafluorophosphate), PyAOP(7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate) and the like. (For more information on activatingand coupling methods see a) M. Bodanszky, A. Bodanszky: The Practice ofPeptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7;b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318; c) F.Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856).

This reaction gives a desired thiazole derivative having formula (I).

Alternatively, a compound having formula (III) is reacted with aso-called halogenating agent such as for example thionyl chloride(SOCl₂). This reaction gives the corresponding carbonyl chloride (IV).

Reaction of a compound having formula (IV) with a compound havingformula R₃R₄NH wherein wherein R₃ and R₄ have the meanings as describedhereinabove gives a thiazole derivative having formula (I). Thisreaction is preferably carried out in the presence of an organic basesuch as for example diisopropylethylamine (DIPEA) or triethylamine.

Alternatively, a compound having formula (II) is reacted in a so-calledamidation reaction with a compound having formula R₃R₄NH wherein R₃ andR₄ have the meanings as described hereinabove to give a thiazolederivative having formula (I). Such amidation reactions can be promotedby the use of trimethylaluminum Al(CH₃)₃ (For more information onaluminum-mediated conversion of esters to amides, see: J. I. Levin, E.Turos, S. M. Weinreb, Synth Commun. (1982), 12, 989-993.)

Alternatively, a compound having formula R₃R₄NH can be reacted with astrong 30 base, such as lithium diisopropylamide (LDA), lithiumhexamethyidisilazide (LiHMDS), potassium hexamethyldisilazide (KHMDS) orsodium hexamethyldisilazide (NaHMDS) and the like to give in situ acompound having formula R₃R₄NLi, R₃R₄NK or R₃R₄NNa, respectively, whichcan then be reacted with a compound having formula (II) to give athiazole derivative having formula (I).

Alternatively, a compound having formula (I) wherein R₃ and R₄ representa hydrogen atom can be reacted with a strong base, such as LDA, LiHMDS,NaH and the like, followed by a reaction with a compound L-R₄ wherein Lrepresents a so-called leaving group such as Br, Cl, I and the like, andR₄ represents a branched or unbranched C₁₋₁₀ alkyl group,cycloalkyl-alkyl group or a branched or unbranched C₃₋₁₀ alkenyl group,which groups may contain one or more heteroatoms from the group (O, N,S) and which groups may be substituted with 1-3 methyl groups, an ethylgroup or 1-3 fluoro atoms.

EXAMPLE 1

Part A: Magnesium (3.04 gram, 0.125 mol) is suspended in anhydrousdiethyl ether (500 mL) under a nitrogen atmosphere and an iodine crystalis added. A solution of 4-chlorobenzyl chloride (20.12 gram, 0.125 mol)in anhydrous diethyl ether (100 mL) is slowly added to maintain a gentlereflux. After cooling the resulting mixture to room temperature asolution of 2,4-dichlorobenzonitrile (17.2 gram, 0.10 mol) in toluene(100 mL) is slowly added. Temperature is raised to 135° C. and thediethyl ether is removed by distillation, toluene is added and theresulting mixture is refluxed for two additional hours. After cooling toroom temperature a solution of HCl (1N, 400 mL) is slowly added undercooling and stirring. The resulting mixture is extracted twice withdiethyl ether, dried over MgSO₄, filtered and concentrated in vacuo.Flash chromatography (dichloromethane) gives2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone as a yellow oil (19.96gram, 67% yield). Crystallisation from cyclohexane gives pure2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone. Melting point: 65-66°C. ¹H-NMR (200 MHz, CDCl₃): δ 7.02-7.45 (m, 7H), 4.22 (s, 2H).

Part B: To a solution of2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.82 gram, 9.42 mmol)in benzene (25 mL) is added bromine (0.48 mL, 1.49 gram, 9.31 mmol) andthe resulting solution is stirred at room temperature for two hours.Dichloromethane is added and the resulting solution is washed withaqueous NaHCO₃ solution. The organic layer is dried over MgSO₄, filteredand evaporated in vacuo to give 3.55 gram (quantitative yield) of2-bromo-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone as a yellowoil (purity˜95% according to HPLC analysis). ¹H-NMR (200 MHz, CDCl₃): δ7.00-7.50 (m, 7H), 6.16 (s, 1H).

Analogously was prepared:

2-Bromo-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethanone. ¹H-NMR (200MHz, CDCl₃): δ 7.95 (d, J=8 Hz, 2H), 7.23-7.62 (m, 5H), 6.77 (s, 1H).

Part C; 2-Bromo-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (9.83gram, 26.0 mmol) and ethyl thiooxamate (5.28 gram, 39.6 mmol) aredissolved in absolute ethanol (50 mL). The resulting red solution isheated at reflux temperature for 4 hours. After evaporation in vacuo thecrude red material (14 gram) is suspended in a mixture ofdichloromethane and methyl-tert-butyl ether. The formed solids areremoved by filtration. The resulting filtrate is purified by columnchromatography (eluant: dichloromethane: R_(f)˜0.4) to giveethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate asa yellow oil (5.21 gram, 48% yield) which slowly solidifies. Meltingpoint: 117-118° C. ¹H-NMR (200 MHz, CDCl₃): δ 7.53, (d, J=2 Hz, 1H),7.40 (dt, J=8 Hz, J=2 Hz, 2H), 7.22-7.35 (m, 4H), 4.52 (q, J=7 Hz, 2H),1.45 (t, J=7 Hz, 3H).

Analogously was prepared:

Ethyl-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)thiazole-2-carboxylate.

Part D;Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate(1.00 gram, 2.42 mmol) is added to 1-aminopiperidine (10 mL) and theresulting stirred mixture is heated at 50° C. for 4 hours.Dichloromethane is added and the resulting solution is washed twice withwater, dried over MgSO₄, filtered and most of the dichloromethane isremoved by evaporation in vacuo. Diisopropyl ether is added and theformed precipitate is removed by filtration. The filtrate isconcentrated in vacuo and purified by flash chromatography (ethylacetate: petroleum ether (40-60)=1:3 (v/v)) to produce5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(1-piperidinyl)thiazole-2-carboxamide(330 mg, 29% yield) as a white foam. ¹H-NMR (400 MHz, CDCl₃): δ 7.92 (s,1H), 7.47 (t, J=2 Hz, 1H), 7.24-7.32 (m, 4H), 7.13 (dt, J=8 Hz, J=2 Hz,2H), 2.85-2.93 (m, 4H), 1.40-1.82 (m, 6H).

Analogously were prepared:

4-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(1-piperidinyl)thiazole-2-carboxamide.Melting point: 190-191° C. ¹H-NMR (400 MHz, CDCl₃): δ 8.03 (s, 1H), 7.51(d, J=2 Hz, 1H), 7.22-7.38 (m, 6H), 2.90-2.97 (m, 4H), 1.75-1.84 (m,4H), 1.44-1.5 (m, 2H).

5-(4-Chlorophenyl)-N-cycloheptyl-4-(2,4-dichlorophenyl)thiazole-2-carboxamide.Melting point: 159-161° C.

5-(4-Chlorophenyl)-N-cyclopentyl-4-(2,4-dichlorophenyl)thiazole-2-carboxamide.Melting point: 111-113° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(trans-4-hydroxycyclohexyl)thiazole-2-carboxamide.Melting point: 109° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(2-methylcyclohexyl)thiazole-2-carboxamide.Melting point: 134-147° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4-fluorobenzyl)thiazole-2-carboxamide.Melting point: 142-144° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(trans4-methylcyclohexyl)thiazole-2-carboxamide.Melting point: 165-166° C.

5-(4-Chlorophenyl)-N-(cis-4-methylcyclohexyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide.Melting point: 72° C.

EXAMPLE 2

40 Part A;Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate(4.10 gram, 9.93 mmol) is suspended in methanol (75 mL). A solution ofKOH (1.98 gram, 30 mmol) in water (75 mL) is added and the resultingmixture is heated at reflux temperature for 2 hours. The resultingyellow solution is allowed to attain room temperature, poured into waterand acidified with 1N aqueous HCl to give a white precipitate. Thisprecipitate is collected by filtration and twice washed with water.Drying in vacuo gives5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid as awhite solid (2.59 gram, 68% yield). ¹H-NMR (200 MHz, DMSO-d₆): δ 9.25(s, 1H), 7.65-7.72 (m, 1H), 7.28-7.52 (m, 6H).

Analogously was prepared:

4-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)thiazole-2-carboxylic acid

Part B; 5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylicacid (1.00 gram, 2.6 mmol) is suspended in anhydrous acetonitrile (20mL) under a nitrogen atmosphere at room temperature.Diisopropylethylamine (DIPEA) (1.36 mL, 7.8 mmol),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (1.08 gram, 2.85 mmol) and O-tert-butylhydroxylamine.HCl (0.35gram, 25.1 mmol) are successively added and the resulting mixture isstirred overnight at room temperature. The resulting mixture isconcentrated in vacuo and dichloromethane is added. The resultingsolution is successively washed with water and brine, dried over MgSO₄,filtered and evaporated in vacuo. Subsequent flash chromatography (ethylacetate:petroleum ether (40-60)=1:3 (v/v)) givesN-(t-butoxy)-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide(0.60 gram, 51% yield) as a white foam. ¹H-NMR (400 MHz, CDCl₃): δ 9.20(s, 1H), 7.47 (t, J=2 Hz, 1H), 7.25-7. (m, 4H), 7.14 (dt, J=8 Hz, J=2Hz, 2H), 1.36 (s, 9H).

Analogously were prepared:

N-(t-Butoxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)thiazole-2-carboxamide.¹H-NMR (400 MHz, CDCl₃): δ 9.23 (s, 1H), 7.52 (d, J=2 Hz, 1H), 7.35 (dt,J=8 Hz, J=2 Hz, 2H) 7.23-7.31 (m, 4H), 1.40 (s, 9H).

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(n-pentyl)thiazole-2-carboxamide¹H-NMR (400 MHz, CDCl₃): δ 7.46 (s, 1H), 7.21-7.32 (m, 5H), 7.14 (dt,J=8 Hz, J=2 Hz, 2H), 3.42-3.48 (m, 2H), 1.59-1.67 (m, 2H), 1.30-1.40 (m,4H), 0.90 (t, J=7 Hz, 3H).

5-(4-Chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)thiazole-2-carboxamide¹H-NMR (400 MHz, CDCl₃): δ 7.46 (s, 1H), 7.24-7.35 (m, 4H), 7.05-7.17(m, 3H), 3.90-4.00 (m, 1H), 1.98-2.07 (m, 2H), 1.72-1.82 (m, 2H),1.14-1.70 (m, 6H).

EXAMPLE 3

Part A; To 4-bromobenzaldehyde (25 gram, 0.135 mol) is successivelyadded 2,4-dichlorophenylacetic acid (27.7 gram, 0.135 mol), aceticanhydride (100 mL) and triethylamine (19 mL, 0.136 mol) and theresulting mixture is heated at reflux temperature for 90 minutes. Thereaction mixture is cooled to 110° C. and water (100 mL) is slowlyadded. The resulting mixture is allowed to attain room temperature andethyl acetate is added. The ethyl acetate layer is twice washed withwater, dried over MgSO₄, filtered and concentrated in vacuo. Theresulting oil is crystallised from diisopropyl ether to give3-(4-bromophenyl)-2-(2,4-dichlorophenyl)acrylic acid as a white solid(26.55 gram, 53% yield).

Part B; 3-(4-Bromophenyl)-2-(2,4-dichlorophenyl)acrylic acid (26.55gram, 71 mmol) is dissolved in anhydrous toluene (130 mL) and theresulting solution is cooled to 0° C. Triethylamine (7.40 gram, 73 mmol)and diphenylphosphoryl azide (19.8 gram, 72 mmol) are successively addedand the resulting mixture Is stirred at 0° C. for 20 minutes and 150minutes at room temperature. The reaction mixture is poured into waterand extracted three times with diethyl ether. The collected organiclayers are dried over MgSO₄ and the diethyl ether Is removed in vacuo.The resulting toluene layer is slowly added to refluxing toluene (150mL). t-Butanol is added after 90 minutes and heating at refluxtemperature is continued for 1 hour, followed by slow addition ofconcentrated hydrochloric acid (5 mL). After stirring the resultingsolution overnight at 90° C. it is allowed to attain room temperature,washed twice with water, dried over MgSO₄, filtered and evaporated invacuo to give a yellow oil. This oil is crystallised from n-hexane togive 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (14.72 gram, 60%yield). Melting point: 69-70° C.

Part C: To a solution of2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (5.00 gram, 15 mmol) inbenzene (50 mL) is dropwise added bromine (0.75 mL, 15 mmol) and theresulting solution is stirred for 4 hours at room temperature andconcentrated in vacuo. Dichloromethane is added and the resultingsolution is washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give2-bromo-2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone as an oil (5.96gram, 94% yield).

Part D: A solution containing2-bromo-2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (5.96 gram, 14mmol) and ethyl thiooxamate (2.80 gram, 21 mmol) in ethanol (30 mL) isheated at reflux temperature for four hours. After cooling to roomtemperature the precipitated crystalline material is removed byfiltration. The filtrate is concentrated in vacuo and the resultingmaterial (7.56 gram orange oil) is purified by flash chromatography(ethyl acetate/petroleum ether=1/3 (v/v)) and subsequently crystallisedfrom diisopropyl ether to afford ethyl5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (2.11gram, 33% yield). Melting point: 129-130° C.

Part E: A stirred mixture containing ethyl5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.00gram, 2.2 mmol) and 1-aminopiperidine (10 mL) is heated overnight at 50°C. The resulting mixture is allowed to attain room temperature,dichloromethane is added and the resulting solution is twice washed withwater, dried over MgSO₄, filtered and concentrated in vacuo to give anoil. Flash chromatographic purification of this oil (ethylacetate/petroleum ether=1/3 (v/v)) gives5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-N-(1-piperidinyl)thiazole-2-carboxamide(870 mg, 78% yield). Melting point: 171-173° C.

Analogously were prepared:

4-(2,4-Dichlorophenyl)-N-(1-piperidinyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxamide.Melting point: 181-183° C.

N-Cyclohexyl-4-(2,4-dichlorophenyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxamide.Melting point: 140-142° C.

4-(2,4-Dichlorophenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxamide.Melting point: 184-185° C.

4-(2,4-Dichlorophenyl)-N-(4-morpholinyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxamide.Melting point: 95° C.

EXAMPLE 4

Part A: Ethyl5-(4-bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.80gram, 3.94 mmol) is dissolved in methanol (20 mL) and a solution of KOH(0.65 gram (85%), 9.85 mmol) in water (20 mL) is added. The resultingmixture is heated at reflux temperature for 1 hour, poured into waterand acidified with hydrochloric acid (1N solution). The formedprecipitated material is collected by filtration and dried in vacuo atroom temperature to give a quantitative yield of5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-thiazole-2-carboxylic acid.Melting point: 94-95° C.

Part B: 5-(4-Bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylicacid (0.50 gram, 1.17 mmol) and diisopropylethylamine (DIPEA) (1.02 mL,5.85 mmol) are dissolved in dichloromethane (5 mL) and cooled to 0° C.7-Aza-1-hydroxybenzotriazole (HOAt) (0.11 gram, 0.81 mmol) and2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP) (0.50 gram,1.76 mmol) are added, followed by addition of n-pentylamine (0.15 gram,1.76 mmol) and the resulting mixture is stirred at room temperatureovernight. Flash chromatographic purification (dichloromethane) gives5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-N-(n-pentyl)thiazole-2-carboxamideas an amorphous solid (0.28 gram, 48% yield).

Analogously were prepared:

5-(4-Bromophenyl)-4-(2,4-dichlorophenyl)-N-(hexahydro(1H)azepin-1-yl)thiazole-2-carboxamide. Melting point: 206-207° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(morpholin-4-yl)thiazole-2-carboxamide.Amorphous solid.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)thiazole-2-carboxamide.Melting point: 179-181° C.

EXAMPLE 5

Part A: To a solution of5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid(0.50 gram, 1.30 mmol) in dichloromethane (10 mL) is successively added1-aminohexahydro(1H)azepine (0.15 gram, 1.30 mmol),7-aza-1-hydroxybenzotriazole (0.18 gram, 1.30 mmol),7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate (PyAOP) (0.68 gram, 1.30 mmol) anddiisopropylethylamine (0.34 mL, 1.95 mmol) and the resulting solution isstirred for 1 hour at room temperature. Concentration In vacuo gives acrude oil (2.01 gram) which is purified by flash chromatography (ethylacetate/petroleum ether=1/3 (v/v)) to give5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(hexahydro(1H)azepin-1-yl)thiazole-2-carboxamide (0.350 gram, 56% yield). Meltingpoint: 185-186° C. (after recrystallisation from diisopropyl ether).

Analogously were prepared:

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(hexahydrocyclopenta-[c]pyrrol-2(1H)-yl)thiazole-2-carboxamide.Melting point: 173-174° C.

N-Benzyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-methyl-thiazole-2-carboxamide.Melting point: 141-144° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4-(trifluoromethyl)benzyl)thiazole-2-carboxamide.Melting point: 174-176° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)thiazole-2-carboxamide.Melting point: 194-195° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(endo-bicyclo[2.2.1]hept-2-yl)thiazole-2-carboxamide.Melting point: 181-183° C.

4-(2,5-Dichlorophenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)-5-(phenyl)thiazole-2-carboxamide.Melting point: 170° C.

N-(Cyclohexyl)-4-(2,5-dichlorophenyl)-5-(phenyl)thiazole-2-carboxamide.Melting point: 75° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(tetrahydro-2H-pyran-2-yloxy)thiazole-2-carboxamide.Melting point: 85° C.

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(5,5,5-trifluoropentyl)thiazole-2-carboxamide.¹H-NMR (400 MHz, CDCl₃): δ 7.47 (br s, 1H), 7.24-7.31 (m, 5H), 7.14 (dt,J=8 Hz, J=2 Hz, 2H), 3.49 (q, J=7 Hz, 2H), 2.07-2.20 (m, 2H), 1.62-1.77(m, 4H).

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(2-fluoroethyl)thiazole-2-carboxamide.Amorphous solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.52-7.58 (m, 1H), 7.47 (brs, 1H), 7.24-7.32 (m, 4H), 7.14 (dt, J=8 Hz, J=2 Hz, 2H), 4.61 (dt, J=47Hz, J=5 Hz, 2H), 3.72-3.84 (m, 2H).

5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(5-fluoropentylthiazole-2-carboxamide.¹H-NMR (400 MHz, CDCl₃): δ 7.47 (br s, 1H), 7.24-7.30 (m, 5H), 7.14 (dt,J=8 Hz, J=2 Hz, 2H), 4.45 (dt, J=47 Hz, J=6 Hz, 2H), 3.45-3.51 (m, 2H),1.64-1.82 (m, 4H), 1.48-1.56 (m, 2H).

4-(2,5-Dichlorophenyl)-N-(4-morpholinyl)-5-(phenyl)thiazole-2-carboxamide.Melting point: 155-157° C.

EXAMPLE 6

5-Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate(1.65 gram, 4.0 mmol) is dissolved in anhydrous THF (25 mL) and aniline(0.37 mL, 4.0 mmol) is added. The resulting solution is cooled to 0° C.and sodium hexamethyidisilazide (4.4 mL of a 1M solution in THF) isadded. The reaction mixture is stirred for 2 hours. Water is added andthe mixture is extracted twice with ethyl acetate. The combined organiclayer is washed with brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue is crystallised from diisopropyl ether to give5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-phenyl-thiazole-2-carboxamide(1.42 g, 77% yield). Melting point: 167-168° C.

EXAMPLE 7

Part A: Gaseous NH₃ is led through a stirred solution of ethyl5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65gram, 4.0 mmol) in methanol (25 mL) at room temperature. A small pieceof sodium metal is added. After stirring the resulting mixture for threehours the precipitate is collected by filtration, washed with a smallportion of methanol and dried to give5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16gram, 76% yield), melting point 195-198° C. ¹H-NMR (200 MHz, CDCl₃): δ7.48 (br s, 1H), 7.22-7.35 (m, 4H), 7.05-7.20 (m, 3H) 5.55-5.65 (M, 1H).

Part B: To a cooled (0° C.) stirred solution of5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16gram, 3.02 mmol) in anhydrous DMF (20 mL) is added NaH (0.13 gram of a60% dispersion) in a nitrogen atmosphere. The resulting mixture isstirred for 1 hour and excess 4,4,4-trifluoro-1-bromobutane (0.7 mL) isadded. The resulting solution is stirred at room temperature for 1 hour,poured onto ice/water and extracted twice with diethyl ether. Thecollected diethyl ether layers are twice washed with water, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue is furtherpurified by column chromatography (silica gel: eluant: dichloromethane)to give5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4,4,4-trifluorobutyl)thiazole-2-carboxamide.Melting point: 99-101° C.

1. A compound of formula (I)

wherein R is chosen from substituent X, wherein X is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₁ is chosen from ahydrogen atom and 1 to 4 substituents X, wherein X is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, mononoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₂ is chosen from: anaphthyl group; and phenyl, thienyl, pyridyl, and pyrimidinyl groups,wherein the phenyl, thienyl, pyridyl, and pyrimidinyl groups mayoptionally be substituted with 1 to 4 substituents X, wherein X ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched orunbranched alkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branchedor unbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₃ is chosen from: ahydrogen atom, a branched or unbranched (C₁₋₁₀)-alkyl orcycloalkyl-alkyl group, a pyridyl group, and a thienyl group; and aphenyl group, a benzyl group, and a phenethyl group, wherein thearomatic rings of the phenyl, benzyl and phenethyl groups may optionallybe substituted with 1 to 5 substituents Z, which can be the same ordifferent, wherein Z is chosen from branched or unbranched (C₁₋₃)-alkylor alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, monoalkyl-(C₁₋₂)-amino,dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido,branched or unbranched (C₁₋₃)-alkylsulfonyl, dimethylsulfamido, branchedor unbranched (C₁₋₃)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl, and acetyl groups; and R₄ is chosen from:branched or unbranched (C₁₋₁₀)-alkyl or cycloalkyl-alkyl groups,branched or unbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl,(C₅₋₁₀)-bicycloalkyl, (C₆₋₁₀)-tricycloalkyl, branched or unbranched(C₃₋₁₀)-alkenyl, and (C₅₋₈)-cycloalkenyl groups, wherein the branched orunbranched (C₁₋₁₀)-alkyl or cycloalkyl-alkyl groups, branched orunbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl,(C₅₋₈)-cycloalkenyl groups may optionally contain at least oneheteroatom chosen from oxygen, nitrogen, and sulphur, and may optionallybe substituted with a substituent chosen from a hydroxy group, 1 to 3methyl groups, an ethyl group, and 1 to 3 fluorine atoms; phenyl,benzyl, and phenethyl groups, wherein the aromatic rings of the phenyl,benzyl and phenethyl groups may optionally be substituted with 1 to 5substituents Z, wherein Z is chosen from branched or unbranched(C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,dimethylsulfamido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, andacetyl groups; pyridyl and thienyl groups; and NR₅R₆ groups, wherein R₅and R₆, together with the nitrogen atom to which they are attached, forma saturated or unsaturated, monocyclic or bicyclic, heterocyclic grouphaving 4 to 10 ring atoms, wherein the heterocyclic group contains atleast one heteroatom chosen from oxygen, nitrogen, and sulphur, and mayoptionally be substituted with a substituent chosen from a branched orunbranched (C₁₋₃)-alkyl group, a hydroxy group, a trifluoromethyl group,and a fluorine atom; or R₃ and R₄, together with the nitrogen atom towhich they are attached, form a saturated or unsaturated, monocyclic orbicyclic, heterocyclic group having 4 to 10 ring atoms, wherein theheterocyclic group contains at least one heteroatom chosen from oxygen,nitrogen, and sulphur, and may optionally be substituted with asubstituent chosen from a branched or unbranched (C₁₋₃)-alkyl group, ahydroxy group, a trifluoromethyl group, and a fluorine atom; orstereoisomers and salts thereof.
 2. A compound of formula (I)

wherein R is substituent Y, wherein Y is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₁ is chosen fromhydrogen and at least one substituent Y, wherein Y is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₂ is chosen from: anaphthyl group; and phenyl, thienyl, pyridyl, and pyrimidinyl groups,wherein the phenyl, thienyl, pyridyl, and pyrimidinyl groups mayoptionally be substituted with at least one substituent Y, wherein Y ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, carboxyl, cyano, carbamoyl, and acetyl groups; R₃is hydrogen; and R₄ is chosen from: branched or unbranched (C₁₋₁₀)-alkylor alkyl-cycloalkyl, branched or unbranched (C₁₋₁₀)-alkoxy,(C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl, (C₁₋₁₀)-tricycloalkyl, branchedor unbranched (C₃₋₁₀)-alkenyl, and (C₅₋₈)-cycloalkenyl groups, whereinthe branched or unbranched (C₁₋₁₀)-alkyl or alkyl-cycloalkyl, branchedor unbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl groups may optionally contain at least oneheteroatom chosen from oxygen, nitrogen, and sulphur, and may optionallybe substituted with a substituent chosen from a hydroxy group, 1 to 3methyl groups, an ethyl group, and 1 to 3 fluorine atoms; benzyl andphenethyl groups, wherein the aromatic rings of the benzyl and phenethylgroups may optionally be substituted with at least one substituent Z,which can be the same or different, wherein Z is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,dimethylsulfamido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, andacetyl groups; pyridyl and thienyl groups; and NR₅R₆ groups, wherein R₅and R₆, together with the nitrogen atom to which they are attached, forma saturated or unsaturated, monocyclic or bicyclic, heterocyclic grouphaving 4 to 10 ring atoms, wherein the heterocyclic group contains atleast one heteroatom chosen from oxygen, nitrogen, and sulphur, and mayoptionally be substituted with a substituent chosen from branched orunbranched (C₁₋₃)-alkyl groups, a hydroxy group, a trifluoromethylgroup, and a fluorine atom; or stereoisomers and salts thereof.
 3. Acompound of formula (I)

wherein R is substituent Y, wherein Y is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₁ is chosen from atleast one substituent Y, wherein Y is chosen from branched or unbranched(C₁₋₃)-alkyl or aikoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino or dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amidoor dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₂ is chosen from: anaphthyl group; and phenyl, thienyl, pyridyl and pyrimidinyl groups,wherein the phenyl, thienyl, pyridyl and pyrimidinyl groups mayoptionally be substituted with one or more substituents Y, wherein Y ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, carboxyl, cyano, carbamoyl, and acetyl groups; R₃is hydrogen; and R₄ is chosen from: branched or unbranched (C₁₋₁₀)-alkylor alkyl-cycloalkyl, branched or unbranched (C₁₋₁₀)-alkoxy,(C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl, (C₆₋₁₀)-tricycloalkyl, branchedor unbranched (C₃₋₁₀)-alkenyl, and (C₅₋₈)-cycloalkenyl groups, whereinthe branched or unbranched (C₁₋₁₀)-alkyl or alkyl-cycloalkyl, branchedor unbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl groups may optionally contain at least oneheteroatom chosen from oxygen, nitrogen, and sulphur, and may optionallybe substituted with a substituent chosen from a hydroxy group, 1 to 3methyl groups, an ethyl group, and 1 to 3 fluorine atoms; benzyl andphenethyl groups, wherein the aromatic rings of the benzyl and phenethylgroups may optionally be substituted with at least one substituent Z,which can be the same or different, wherein Z is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,dimethylsulfamido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, andacetyl groups; pyridyl and thienyl groups; NR₅R₆ groups, wherein R₅ andR₆, together with the nitrogen atom to which they are attached, form asaturated or unsaturated, monocyclic or bicyclic, heterocyclic grouphaving 4 to 10 ring atoms, wherein the heterocyclic group contains atleast one heteroatom chosen from oxygen, nitrogen, and sulphur, and mayoptionally be substituted with a substituent chosen from a branched orunbranched (C₁₋₃)-alkyl group, a hydroxy group, a trifluoromethyl group,and a fluorine atom; or stereoisomers and salts thereof.
 4. A compoundof formula (I)

wherein R is a halogen atom; R₁ is chosen from at least one substituentY, wherein Y is chosen from branched or unbranched (C₁₋₃)-alkyl oralkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, monoalkyl-(C₁₋₂)-amino,dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido,branched or unbranched (C₁₋₃)-alkoxycarbonyl, carboxyl, cyano,carbamoyl, and acetyl groups; R₂ is chosen from: a naphthyl group; andphenyl, thienyl, pyridyl and pyrimidinyl groups, wherein the phenyl,thienyl, pyridyl and pyrimidinyl groups may optionally be substitutedwith at least one substituent Y, wherein Y is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₃ is hydrogen; and R₄ ischosen from: branched or unbranched (C₁₋₁₀)-alkyl or alkyl-cycloalkyl,branched or unbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl,(C₅₋₁₀)-bicycloalkyl, (C₆₋₁₀)-tricycloalkyl, branched or unbranched(C₃₋₁₀)-alkenyl, and (C₅₋₈)-cycloalkenyl groups, wherein the branched orunbranched (C₁₋₁₀)-alkyl or alkyl-cycloalkyl, branched or unbranched(C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl groups may optionally contain at least oneheteroatom chosen from oxygen, nitrogen, and sulphur, and may optionallybe substituted with a substituent chosen from a hydroxy group, 1 to 3methyl groups, an ethyl group, and 1 to 3 fluorine atoms; benzyl andphenethyl groups, wherein the aromatic rings of the benzyl and phenethylgroups may optionally be substituted with at least one substituent Z,which can be the same or different, wherein Z is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,dimethylsulfamido, branched or unbranched (C₁₋₃)-alkoxycarbonylcarboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl andacetyl groups; pyridyl and thienyl groups; and NR₅R₆ groups, wherein R₅and R₆ together with the nitrogen atom to which they are attached form asaturated or unsaturated, monocyclic or bicyclic, heterocyclic grouphaving 4 to 10 ring atoms, wherein the heterocyclic group contains atleast one heteroatom chosen from oxygen, nitrogen, and sulphur, and mayoptionally be substituted with a substituent chosen from a branched orunbranched (C₁₋₃)-alkyl group, a hydroxy group, a trifluoromethyl group,and a fluorine atom; or stereoisomers and salts thereof.
 5. A compoundof formula (I)

wherein R is a halogen atom R₁ is chosen from at least one substituentY, wherein Y is chosen from branched or unbranched (C₁₋₃)-alkyl oralkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, monoalkyl-(C₁₋₂)-amino,dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido,branched or unbranched (C₁₋₃)-alkoxycarbonyl, carboxyl, cyano,carbamoyl, and acetyl groups; R₂ is chosen from: a naphthyl group; andphenyl, thienyl, pyridyl, and pyrimidinyl groups, wherein the phenyl,thienyl, pyridyl, and pyrimidinyl groups may optionally be substitutedwith at least one substituent Y, wherein Y is chosen from branched orunbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl and acetyl groups; R₃ is hydrogen; and R₄ ischosen from NR₅R₆ groups, wherein R₅ and R₆, together with the nitrogenatom to which they are attached, form a saturated or unsaturated,monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms,wherein the heterocyclic group contains at least one heteroatom chosenfrom oxygen, nitrogen, and sulphur, and may optionally be substitutedwith a substituent chosen from a branched or unbranched (C₁₋₃)-alkylgroup, a hydroxy group, a trifluoromethyl group, and a fluorine atom; orstereoisomers and salts thereof.
 6. A compound of formula (I)

wherein R is a halogen atom; R₁ is chosen from at least one halogenatom; R₂ is chosen from: a naphthyl group; and phenyl, thienyl, pyridylor pyrimidinyl groups, wherein the phenyl, thienyl, pyridyl andpyrimidinyl groups may optionally be substituted with at least onesubstituent Y, wherein Y is chosen from branched or unbranched(C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, cyano, carbamoyl, and acetyl groups; R₃ is hydrogen; and R₄ ischosen from NR₅R₆ groups, wherein R₅ and R₆, together with the nitrogenatom to which they are attached, form a saturated or unsaturated,monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms,wherein the heterocyclic group contains at least one heteroatom chosenfrom oxygen, nitrogen, and sulphur, and may optionally be substitutedwith a substituent chosen from a branched or unbranched (C₁₋₃)-alkylgroup, a hydroxy group, a trifluoromethyl group, and a fluorine atom; orstereoisomers and salts thereof.
 7. A method of treating at least onedisorder involving CB₁ cannabinoid neurotransmission or neurologicaldisorders, wherein said disorder is chosen from anxiety, depression,appetite disorders, obesity, and pain, comprising: administering to apatient in need of treatment an effective amount of at least onecompound of formula (I):

wherein R is chosen from a hydrogen atom and a substituent X, wherein Xis chosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched orunbranched alkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branchedor unbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₁ is chosen from ahydrogen atom and 1 to 4 substituents X, wherein X is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₂ is chosen from: anaphthyl group; and phenyl, thienyl, pyridyl and pyrimidinyl groups,wherein the phenyl, thienyl, pyridyl and pyrimidinyl groups mayoptionally be substituted with 1 to 4 substituents X, wherein X ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched orunbranched alkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branchedor unbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₃ is chosen from: ahydrogen atom, a branched or unbranched (C₁₋₁₀)-alkyl orcycloalkyl-alkyl group, a pyridyl group, and a thienyl group; andphenyl, benzyl and phenethyl groups, wherein the aromatic rings of thephenyl, benzyl and phenethyl groups may optionally be substituted with 1to 5 substituents Z, which can be the same or different, wherein Z ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkylsulfonyl, dimethylsulfamido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,carbamoyl, sulfamoyl, and acetyl groups; and R₄ is chosen from: branchedor unbranched (C₁₋₁₀)-alkyl or cycloalkyl-alkyl group, branched orunbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl groups, wherein the branched or unbranched(C₁₋₁₀)-alkyl or cycloalkyl-alkyl group, branched or unbranched(C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl groups may optionally contain at least oneheteroatom chosen from oxygen, nitrogen, and sulphur, and may optionallybe substituted with a substituent chosen a hydroxy group, 1 to 3 methylgroups, an ethyl group, and 1 to 3 fluorine atoms; phenyl, benzyl, andphenethyl groups, wherein the aromatic rings of the phenyl, benzyl, andphenethyl groups may optionally be substituted with 1 to 5 substituents7, wherein Z is chosen from branched or unbranched (C₁₋₃)-alkyl oralkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, monoalkyl-(C₁₋₂)-amino,dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido,branched or unbranched (C₁₋₃)-alkylsulfonyl, dimethylsulfamido, branchedor unbranched (C₁₋₃)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl, and acetyl groups; pyridyl and thienylgroups; and NR₅R₆ groups, wherein R₅ and R₆, together with the nitrogenatom to which they are attached, form a saturated or unsaturated,monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms,wherein the heterocyclic group contains at least one heteroatom chosenfrom oxygen, nitrogen, and sulphur, and may optionally be substitutedwith a substituent chosen from a branched or unbranched (C₁₋₃)-alkylgroup, a hydroxy group, a trifluoromethyl group, and a fluorine atom; orR₃ and R₄, together with the nitrogen atom to which they are attached,form a saturated or unsaturated, monocyclic or bicyclic, heterocyclicgroup having 4 to 10 ring atoms, wherein the heterocyclic group containsat least one heteroatom chosen from oxygen, nitrogen, and sulphur, andmay optionally be substituted with a substituent chosen from a branchedor unbranched (C₁₋₃)-alkyl group, a hydroxy group; a trifluoromethylgroup, and a fluoro atom; or stereoisomers, and salts thereof.
 8. Apharmaceutical composition comprising at least one active componentchosen from a compound of formula (I),

wherein R is chosen from substituent X, wherein X is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,mono-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₁ is chosen from ahydrogen atom and 1 to 4 substituents X, wherein X is chosen frombranched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl and acetyl groups; R₂ is chosen from: anaphthyl group; and phenyl, thienyl, pyridyl, and pyrimidinyl groups,wherein the phenyl, thienyl, pyridyl, and pyrimidinyl groups mayoptionally be substituted with 1 to 4 substituents X, wherein X ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched orunbranched alkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branchedor unbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; R₃ is chosen from: ahydrogen atom, a branched or unbranched (C₁₋₁₀)-alkyl orcycloalkyl-alkyl group, a pyridyl group, and a thienyl group; andphenyl, benzyl, and phenethyl groups, wherein the aromatic rings of thephenyl, benzyl, and phenethyl groups may optionally be substituted with1 to 5 substituents Z, which can be the same or different, wherein Z ischosen from branched or unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino,monoalkyl-(C₁₋₂)-amido, dialkyl-(C₁₋₂)-amido, branched or unbranched(C₁₋₃)-alkylsulfonyl, dimethylsulfamido, branched or unbranched(C₁₋₃)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,carbamoyl, sulfamoyl, and acetyl groups; and R₄ is chosen from: branchedor unbranched (C₁₋₁₀)-alkyl or cycloalkyl-alkyl groups, branched orunbranched (C₁₋₁₀)-alkoxy, (C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl,(C₆₋₁₀)-tricycloalkyl, branched or unbranched (C₃₋₁₀)-alkenyl, and(C₅₋₈)-cycloalkenyl, wherein the branched or unbranched (C₁₋₁₀)-alkyl orcycloalkyl-alkyl groups, branched or unbranched (C₁₋₁₀)-alkoxy,(C₃₋₈)-cycloalkyl, (C₅₋₁₀)-bicycloalkyl, (C₆₋₁₀)-tricycloalkyl, branchedor unbranched (C₃₋₁₀)-alkenyl, (C₅₋₈)-cycloalkenyl groups may optionallycontain at least one heteroatom chosen from oxygen, nitrogen, andsulphur, and may optionally be substituted with a substituent chosenfrom a hydroxy group, 1 to 3 methyl groups, an ethyl group, and 1 to 3fluorine atoms; phenyl, benzyl, and phenethyl groups, wherein thearomatic rings of the phenyl, benzyl and phenethyl groups may besubstituted with 1 to 5 substituents Z, wherein Z chosen from branchedor unbranched (C₁₋₃)-alkyl or alkoxy, hydroxy, halogen trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkylsulfonyl,dimethylsulfamido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, andacetyl groups; pyridyl and thienyl groups; and NR₅R₆ groups, wherein R₅and R₆, together with the nitrogen atom to which they are attached, forma saturated or unsaturated, monocyclic or bicyclic, heterocyclic grouphaving 4 to 10 ring atoms, wherein the heterocyclic group contains atleast one heteroatom chosen from oxygen, nitrogen, and sulphur, and mayoptionally be substituted with a substituent chosen from a branched orunbranched (C₁₋₃)-alkyl group, a hydroxy group, a trifluoromethyl group,and a fluorine atom; or R₃ and R₄, together with the nitrogen atom towhich they are attached, form a saturated or unsaturated, monocyclic orbicyclic, heterocyclic group having 4 to 10 ring atoms, wherein theheterocyclic group contains at least one heteroatom chosen from fromoxygen, nitrogen, and sulphur, and may optionally be substituted with asubstituent chosen from a branched or unbranched (C₁₋₃)-alkyl group, ahydroxy group, a trifluoromethyl group, and a fluorine atom; orstereoisomers and salts thereof.
 9. A compound of formula (V)

wherein R₂ is chosen from: a naphthyl group; and phenyl, thienyl,pyridyl, and pyrimidinyl groups, wherein the phenyl, thienyl, pyridyl,and pyrimidinyl groups may optionally be substituted with 1 to 4substituents X, wherein X is chosen from branched or unbranched(C₁₋₃)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, nitro, amino,monoalkyl-(C₁₋₂)-amino, dialkyl-(C₁₋₂)-amino, monoalkyl-(C₁₋₂)-amido,dialkyl-(C₁₋₂)-amido, branched or unbranched (C₁₋₃)-alkoxycarbonyl,trifluoromethylsulfonyl, sulfamoyl, branched or unbranchedalkyl-(C₁₋₃)-sulfonyl, carboxyl, cyano, carbamoyl, branched orunbranched dialkyl-(C₁₋₃)-aminosulfonyl, branched or unbranchedmonoalkyl-(C₁₋₃)-aminosulfonyl, and acetyl groups; and R₈ is chosen froma hydroxy group, a branched or unbranched (C₁₋₄)-alkoxy group, abenzyloxy group, and a chlorine atom.